Nanette K. Wenger, MD; Sandra J. Lewis, MD; David M. Herrington, MD; Vera Bittner, MD; Francine K. Welty, MD, PhD; Treating to New Targets Study Steering Committee and Investigators
Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, Treating to New Targets Study Steering Committee and Investigators. Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease. Ann Intern Med. 2007;147:1-9. doi: 10.7326/0003-4819-147-1-200707030-00002
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Published: Ann Intern Med. 2007;147(1):1-9.
Data on the benefits of intensive lipid-lowering treatment for elderly persons with heart disease are sparse.
This secondary analysis of a trial examined outcomes of 3809 adults 65 years of age or older with coronary heart disease who were randomly assigned to receive atorvastatin, 80 or 10 mg/d. Patients achieved average low-density lipoprotein cholesterol levels of approximately 1.81 mmol/L (70 mg/dL) and 2.59 mmol/L (100 mg/dL), respectively. Fewer patients who received 80 mg of atorvastatin had major fatal or nonfatal cardiovascular events than did those who received 10 mg of atorvastatin (10.3% vs. 12.6%).
The researchers could not determine whether benefits were due to the higher statin dose, lower achieved cholesterol levels, or both factors.
To convert LDL cholesterol values to mg/dL, divide by 0.02586. To convert triglyceride values to mg/dL, divide by 0.01129.
The hazard ratio for a major cardiovascular event is 0.81 (95% CI, 0.67 to 0.98) (P = 0.03) among patients 65 years of age or older and 0.76 (CI, 0.64 to 0.90) (P = 0.001) among patients younger than 65 years of age. The hazard ratio for fatal or nonfatal stroke is 0.79 (CI, 0.57 to 1.09) (P = 0.158) and 0.70 (CI, 0.49 to 1.00) (P = 0.048), respectively.
CA = cardiac arrest; CHD = coronary heart disease; CHF = congestive heart failure; CV = cardiovascular; MI = myocardial infarction; PAD = peripheral artery disease; PR = procedure-related. *P value for heterogeneity (patients ≥65 years vs. patients <65 years).
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robert a. alter
July 6, 2007
65 years or older does not equal 65 to 75
The title of the Wegner, NK et.al. article is misleading. The study design of the TNT study notes a maximum age of 75. Hence, a more accurate title would replace "in patients 65 years of age or older" with "in patients 65 to 75 years of age". All of the figures and tables should include similar language. Such figures and tables are often cited and pictured in articles, textbooks and advertisements without a description of the study population. When the study population age is clearly defined, imprecise terms that inappropriately generalize the results should be avoided.
Roy C Ziegelstein
Johns Hopkins University School of Medicine
July 8, 2007
Isn't 80 Considered 65 Years of Age or Older?
About 1 of every 100 Americans is an individual at least 80 years old with coronary heart disease. This fact will not surprise the internists, geriatricians, and cardiologists across the country who care for these patients. The United States Census Bureau's statistics,1 indicate that as of 2005, there were 288,378,137 people in this country. Of the 141,274,964 men, 2.4% were 80 years of age and older and of the 147,103,173 women, that percentage was 3.9%. The American Heart Association tells us that 32.7% and 21.6% of men and women, respectively, 80 years of age and older have coronary heart disease.2 Taking a moment to do the math, one finds that 1,108,726 men and 1,239,197 women 80 years of age and older have cardiovascular disease in this country, approximately 1% of the population. And we should recall that the US Census Bureau data excludes individuals who reside in institutions; if it did not, these numbers would be far greater.
The report by Wenger, et al. from the Treating to New Targets (TNT) study3 shows that intensive lowering of low-density lipoprotein cholesterol has advantages in some patients 65 years of age or older with stable coronary heart disease, but it does not address any of the almost 2.5 million individuals over age 80 or even the many individuals with coronary heart disease who are 76 to 79 years of age. No doubt, though, many clinicians will extrapolate the data in the study by Wenger et al.3 to all individuals over age 65 with stable coronary heart disease. And who could really blame a clinician who, after reading this study, recommends an increase in statin dose for an 83 year-old with stable coronary heart disease and a low-density lipoprotein cholesterol level of 94 mg/dL? After all, the title of the article, the abstract, and the manuscript itself all indicate that the study group is comprised of "patients 65 years of age or older" with no mention, except for a single line in the Methods, that only individuals up to 75 years of age were included in this study. This important limitation should be highlighted, and clinicians should be cautioned not to extrapolate the results of this study to the many individuals with stable coronary disease who are older than 75 years of age.
1. United States 2005 American Community Survey. Accessed at http://factfinder.census.gov/servlet/STTable?_bm=y&-geo_id=01000US&- qr_name=ACS_2005_EST_G00_S0101&-ds_name=ACS_2005_EST_G00_ on 8 July 2007.
2. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69-171.
3. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK; Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1-9.
Cardiology Service, Ospedale di San Vito al Tagliamento, Italy
July 10, 2007
Concerns about efficacy and safety of high-dose atorvastatin.
TO THE EDITOR "“ When making therapeutic decisions, physicians need to balance benefits, risks and costs. We feel that the application in clinical practice of the suggestions by Wenger and colleagues from the Treating to New Targets (TNT) study (1) may be very hard. The TNT study (2) screened 18,468 patients up to 75 years, but after an ingenious selection and an open-label run-in phase, only 10,003 persons were randomized, thus excluding patients with concomitant medical conditions which might increase the risk of statin-related side-effects, and persons with major comorbidities: in clinical practice, the drug may be given to most of these patients. Notwithstanding these criteria of selection, the reduction of major fatal or nonfatal cardiovascular events (2,3%) in patients 65 to 75 years of age were lower than the increase in treatment- related adverse events (3,1%). Furthermore, although the TNT study (1, 2) was neither designed nor powered to detect a reduction in all-cause mortality (but why not?), it's disturbing to note that high-dose atorvastatin in the secondary prevention of cardiovascular disease does not improve survival when compared to a very lower dose.
1. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK; Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1-9.
2. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C; TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004; 93: 154-8.
Comando Brigata alpina Julia, Udine 33100 Italy
Failure of atorvastatin [LipitorÂ®] to save lives.
The analysis of the TNT trial by Wenger et al (1) suggests benefit in over 65 year old cardiac patients from top-dose atorvastatin. However, the 22 more deaths from noncardiovascular causes more than offset the 5 fewer deaths from cardiovascular causes (versus patients on low dose), a result consistent with the entire TNT study population.
This is ominous considering that this subgroup had the following characteristics at baseline: mean age 70 years, 82% had suffered angina,18% had diabetes, 53% had suffered a myocardial infarction, 49% angioplasty and 55% bypass operations.
Since stable angina is a non-fatal pain, the significant reduction in angina in the ASCOT study (2) may well underlie much of the non-fatal 'event' benefit of this and other trials and that reported no mortality benefit from atorvastatin, versus placebo.
When 'event' benefit may result from the amount of hospital visits but without lowering all cause mortality, we are clearly dealing with symptoms and not with causes. This should be made clear in statin stake- holder written articles, such as the one in question, especially when not presenting discordant evidence.
Another placebo controlled trial, SPARCL (3), ended with non significantly more deaths on top dose atorvastatin and the sponsor of the TNT trial, Pfizer, in March 2007 refused [letter on file] to release the mortality data regarding 49 in-house atorvastatin studies (4).
There are no placebo controlled trials or meta-analysis that show a mortality benefit from statin treatment in women (5). It is thus unfortunate that the authors did not publish the Kaplan-Meier all-cause mortality curves regarding both women and men in the TNT study and this in the same fashion as Figure 2 of the article in question.
While the authors suggest but do not prove benefit from more aggressive treatment, the main purpose of cardiologists is preventing deaths. Here, the role of atorvastatin should be clearly reported to gender and age-based patient groups whose motivation to take atorvastatin may be the belief that it may prolong their lives, which is not the case based the trial data published so far. The release of the relevant age and gender based Kaplan-Meier mortality curves would help patients and prescribers.
Luca Mascitelli, M.D., Udine, Italy
Eddie Vos, M. Eng, Sutton (Qc) Canada
1. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007; 147: 1-9. Medline 17606955
2. Sever PS, DahlÃ¶f B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, et al Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than- average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361: 1149-58. Medline 12686036
3. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med.; 355: 549-59. Medline 16899775
4. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006; 97: 61-7. Medline 16377285
5. Vos E, Rose CP. Questioning the benefits of statins. CMAJ. 2005; 173: 1207. Medline 16275976
Mark R. Goldstein
Are We Trading Heart Disease for Cancer?
In their secondary analysis of the Treating to New Targets (TNT) study, the investigators concluded that the findings support the use of intensive low-density lipoprotein-cholesterol lowering therapy in elderly individuals with established cardiovascular disease (1). Close scrutiny of the data contradict their conclusion.
The secondary analysis of TNT compared the outcomes using either atorvastatin 10 mg daily or 80 mg daily in the 3809 patients 65 years of age or older for the 4.9 year study duration. The overall rate of death over the duration of the study was 9.1% in subjects randomized to 80 mg of atorvastatin daily and 8.5% in subjects randomized to 10 mg of atorvastatin daily.
The trend towards increased death in the high-dose atorvastain group was largely due to an increase in cancer death, which was 2.8% in that group and 2.1% in the low- dose atorvastatin group. Coronary heart disease death was 3.0% in the high-dose atorvastin group and 3.3% in the low-dose atorvastatin group.
Therefore, the increase in cancer death was greater than the decrease in coronary heart disease death in the high-dose atorvastatin group. Perhaps, the investigators can provide additional data on the incidence of new non-fatal cancer dignoses in each group, just as they provided data on non-fatal coronary heart disease events.
Other trials have demonstrated an increase in cancer incidence and death in elderly subjects randomized to statins compared to placebo, which cancelled any mortality benefit of decreasing coronary heart disease (2). The TNT study suggests that there might be a dose response of statin therapy in increasing cancer in elderly subjects.
With these uncertainties, the suggestion that this study supports the use of intensive low-density lipoprotein cholesterol-lowering therapy in elderly subjects with established cardiovascular disease is on shaky grounds.
1) Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, for the Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007; 147: 1-9.
2) Shepherd J, Blauw GJ, Murphy MB, et al, on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360: 1623-30.
William B. Greenough
Johns Hopkins Bayview Medical Center
July 11, 2007
Response to Wenger and colleagues
To the Editor:
Wenger and colleagues' secondary analysis of atorvastatin in elderly patients with coronary heart disease shows that both death and resuscitation from cardiac arrest were more likely in the group of patients assigned to high-dose atorvastatin. Neither difference was significant.
Since atorvastatin might make it more likely that your heart will stop, it seems perhaps premature to tout "additional clinical benefit". The authors do acknowledge 6 contributors who collected and analyzed data, all Pfizer employees, and a medical writer, and all authors get money from Pfizer. We impute no sinister motives, but wonder whether the phrase "clinical benefit" originated with the authors or their writer.
William B. Greenough Thomas E. Finucane
LAC+USC Medical Center
July 12, 2007
Inflammation and Statin Myopathy: Is the future rosy for atorvastatin?
It is with great interest that we reviewed the article "Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease" by Wenger et al. However, there are several areas for which further elucidation would be of benefit. As a medical resident currently on a Rheumatology teaching service we have seen several adverse events to statins in consultation.
Our concerns are as follows-
First, in clinical practice we would be apprehensive to start patients especially the elderly on very high dose statins as initial therapy due to perceived higher discontinuation rates secondary to a greater incidence of "muscle cramps". In our clinical experience we often stop the statins when they are having symptoms with a mildly elevated CPK. Such patients rarely return to the initial statin and often are reluctant to change to newer agent at any dose. Only once have seen a 10 fold increase in CPK, wherein the patient's CPK was >80,000 and was quite ill. Subsequent work up revealed polymyositis which ultimately was felt to be unrelated to his statin use. It is widely known that the high dose of statins especially in elderly population is related to increased incidence of statin-induced myopathy which was not touched upon in the article which only states that "adverse events" were about 3.1%. We feel that true clinical incidence of statin related myopathy is under-reported using the " greater than 10 fold increase in CPK" criteria.
Second, the role of inflammation as measured by CRP in MI is a key area of investigation for cardiac morbidity and mortality. Unfortunately, this was not measured in this large otherwise well designed study emphasizing CHD risk. In Rheumatology, statins have been investigated in RA for potential benefits which may add to the significance of inflammation in lipid lowering therapy.
Third, we agree with prior correspondants that the higher cancer rates are an area of concern.
Overall, despite our initial excitement in reading this article there are several gray areas. Hopefully, future studies will include the role of inflammation and myopathic events in high dose statin therapy.
Nanette K Wenger
Emory University School of Medicine
August 15, 2007
We thank Drs. Alter, Mascitelli, Vos, Eng, and Goldstein for their careful review of our manuscript. Treatment effect was qualitatively similar in subjects 35-64 and 65-75 years providing some reassurance that age does not importantly modify treatment effect. With a treatment duration of 4.9 years, some follow-up derived from subjects >75 years. Nonetheless, we concur that TNT does not provide definitive efficacy or safety information for the 5% of the U.S. population >75 years. A manuscript comparing outcomes by gender is currently under review.
The primary study outcome for TNT overall and this subanalysis was time to first occurrence of a major cardiovascular event: CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. Angina was not included in the primary TNT endpoint and neither the overall trial nor this subanalysis were powered to determine if small differences in total mortality were real or simply due to the play of chance. Apparent differences in total and noncardiovascular mortality between subgroups should be interpreted with great caution, especially in an older population where competing causes of death (such as cancer) closer to the end of normal lifespan are likely to play a larger role. Analyses by type of cancer in this and other statin trials do not show any organ specificity [2,3]. Ancillary analysis of noncardiovascular mortality in TNT  showed no relationship between cancer mortality and achieved LDL-C level; participants in the lowest quintile of achieved LCL-C (the majority taking 80 mg atorvastatin) had the lowest cancer mortality . Data on incidence of nonfatal cancer by age subgroup is not available. Given study design and power, such analyses are unlikely to yield definitive results. We agree that our study does not support intensive lipid-lowering therapy among older or younger patients to reduce total mortality; but mortality should not be the sole measure of treatment benefit. Nonfatal cardiovascular events such as myocardial infarction and stroke significantly impact functional status and quality of life, worsen prognosis, and result in substantial health care expenditures. We affirm our conclusion that intensive lipid-lowering therapy in patients with established CHD 65 years of age or older (atorvastatin 80 mg vs. atorvastatin 10 mg daily) prevents potentially disabling cardiovascular events, with an absolute risk reduction comparable to that in younger individuals.
REFERENCES 1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-35.
2. Shepherd J, Blauw GJ, Murphy MB et al. on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360: 1623- 30.
3. LaRosa JC, Grundy SM, Kastelein JJP, Kostis JB, Greten H, on behalf of the Treating to New Targets (TNT) Steering Committee and Investigators. Safety and efficacy of atorvastatin-induced very low- density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the Treating to New Targets (TNT) study. Am J Cardiol In Press, 2007.
Vera Bittner, David Herrington, and Nanette Wenger, on behalf of the Treating to New Targets (TNT) Steering Committee and Investigators.
August 29, 2007
Reply to Drs. Greenough and Finucane
The term "clinical benefit" derives from the primary TNT manuscript as written by the trial Steering Committee, NEJM 352:1425, 2005.
We call to your attention the attestations of the authors on the final page of the Annals manuscript of their contributions to conception and design, analysis and interpretation of the data, drafting of the article, clinical revision of the article for important intellectual content, final approval of the article, and correction and assembly of data.
Francine K. Welty, M.D. Sandra J. Lewis, M.D. Nanette K. Wenger, M.D.
See original manuscript
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